Migraine is the most common headache causing patients to consult a physician. According to the American Migraine Study II, approximately 28 million people in the United States aged 12 and older (approximately 13 percent of the population) suffer from headaches that fit the medical definition of migraine established by the International Headache Society. This corresponds to one migraine sufferer in every four U.S. households. The percentage of patients whose headaches fit the medical definition of migraine who are being diagnosed has increased compared to a decade ago. A majority of all migraine sufferers (53 percent) characterize their pain as causing either severe impairment or forcing them to retreat to their beds sometimes for days at a time. There have been no dramatic changes in the way physicians approach the treatment of migraine in the past 10 years. (Lipton et al., Headache 41:638-645, 646-657 (2001)),
A three-item Identification of Migraine (ID Migraine) clinical decision rule for the diagnosis of migraine has been developed (Stewart et al., Neurology 44(6 suppl 4):S17-23 (1994)). A migraine is a type of primary headache that some people get repeatedly over time. Migraines are different from other headaches because they occur with symptoms such as nausea, vomiting, or sensitivity to light. In most people, a throbbing pain is felt only on one side of the head. Migraines are classified as either “with aura” or “without aura.” An aura is a group of neurological symptoms, usually vision disturbances that serve as warning sign. Patients who get auras typically see a flash of brightly colored or blinking lights shortly before the headache pain begins. However, most people with migraines do not have such warning signs.
Multiple humoral agents have been postulated as being the major factor in migraine. These include serotonin, histamine, prostaglandins, platelet factors, endorphins, and vasoactive neuropeptides. The etiology of migraine has been studied by many investigators. Present research no longer fully supports the vasodilator/vasoconstrictor mechanism of vascular headache, i.e., arterial dilation causes pain and constriction equals relief. Research also has now implicated a sterile inflammation, possibly occurring in the dura mater, as the causative factor for vascular head pain. An unknown trigger activates perivascular trigeminal axons, which release vasoactive neuropeptides (substance P, calcitonin gene-related peptide, etc.). These agents produce the local inflammation, i.e., vasodilation, plasma extravasation and mast cell degranulation, which cause transmission of impulses to the brain stem and higher centers which in turn register as head pain (Moskowitz, M. A., Trends Pharmacol. Sci. 13:307-311 (1992)).
Migraine therapy is either prophylactic or acute (symptomatic). Prophylactic medication may be selected for a patient having two to four or more headaches per month, if they are severe enough to interfere with daily activities. Beta blockers such as propranolol are the most commonly used. Other medications frequently used include serotonin antagonists such as methysergide, calcium channel blockers, amytryptyline, and ergotamine preparations with belladona alkaloids and phenobarbital. All of these medications have significant side effects including sedation, loss of energy and drive, dry mouth, constipation, weight gain, and gastrointestinal cramping and distress. More recently, multiple injections of the bacterial toxin onabotulinumtoxinA have been indicated for the treatment of chronic migraine. For symptomatic treatment, ergotamine with caffeine is commonly used. Other medications employed for treating migraine include isometheptene, non-steroidal anti-inflammatory drugs, dihydroergotamine and the newer triptans, such as sumatriptan, etc. When narcotics, such as butalbital with codeine are used frequently, additional hazards, including the considerable potential for rebound headaches and habituation are encountered.
The administration of serotonin agonists is well established for the treatment of migraine headache. The serotonin agonist class that is most widely prescribed is the triptan class, including sumatriptan, zolmitriptan, naratriptan, rizatriptan, eletriptan, frovatriptan and almotriptan. These compounds bind specifically to serotonin 5-HT1D/1B receptors. To a lesser degree, ergot alkaloids such as ergotamine and dihydroergotamine (DHE) are also used to treat a variety of disease states, including, but not limited to the acute treatment of migraine.
Dihydroergotamine (DHE) was identified as an effective treatment for migraine nearly fifty years ago (Raskin, Neurology 36:995-997 (1986); Silberstein, et al., Headache 30:334-339 (1990); Saadah, Headache 32:18-20 (1992); and Winner, Headache 33:471-475 (1993)). DHE has been administered by intramuscular (IM) or intravenous (IV) injection for over 50 years (Belgrade, et al., Neurology 39:590-592 (1989) and Winner, Headache 33:471-475 (1993)). More recently, DHE has been administered using alternative delivery techniques such as intranasal (IN) administration or subcutaneous (SC) injection (Klapper, et al., Headache 32:21-23 (1992); Winner, et al., Arch. Neurol. 53:180-184 (1996); and Becker, et al., Headache 36:144-148 (1996)). In addition, an oral inhalation dosage form of DHE has been developed that is administered using a breath-actuated, pressurized metered dose inhaler (pMDI) device (U.S. Publication No. US2008/0287451 to Cook et al.).
Although effective in the treatment of migraine, DHE administration is often accompanied by side effects such as nausea, vomiting and chest pain (Winner, et al., Arch. Neurol. 53:180-184 (1996)). Other side effects observed from postmarketing experience in patients receiving DHE injection include vasospasm, paraesthesia, hypertension, dizziness, anxiety, dyspnea, headache, flushing, diarrhea, rash, increased sweating, cardiac valvulopathy, and pleural and retroperitoneal fibrosis seen after long-term use of dihydroergotamine. At least one side effect, nausea, occurs more frequently after intravenous administration than after intramuscular or intranasal administration. When given subcutaneously at a concentration of only 1.5 mM, DHE has been reported to cause nausea in nearly 16% of treated patients (Winner, et al., Arch. Neurol. 53: 180-184 (1996)). The currently accepted treatment algorithms for injection or IV use of DHE call for the administration of an antiemetic prior to or concurrent with administration of DHE to prevent nausea. Due to the possibility for fibrotic side effects, patients with known cardiovascular disease are not qualified to receive IV DHE treatment. Notwithstanding the potential for such undesirable side effects, DHE is still considered the “gold standard” for treatment of severe migraine, cluster headache, and chronic daily headache.
With regard to considerations of absorption, distribution, metabolism, and excretion (ADME), DHE has a very low oral bioavailability (i.e., from 1-3%) due to a high first-pass metabolism and incomplete drug passage across the gastrointestinal mucosa (Little et al., Br J Clin Pharmacol. 15:785-790 (1982)), whereas the bioavailability of IM DHE is 100%, and about 40% following IN administration (Silberstein et al. Headache 43:144-166 (2003)). Although little is known about human tissue distribution, DHE can be found distributed in high concentrations in the liver, lung and kidney after oral or IV administration in rats. DHE is quickly and extensively metabolized in the liver, and only about 6-7% of an IM administered DHE dose is extracted in the urine. The major elimination route is in the feces following biliary excretion of the parent DHE and its metabolites. (Silberstein et al. Headache 43:144-166 (2003)). Four DHE metabolites have been identified in human plasma following oral administration (Maurer et al., Pharmacology 26:463-470 (1984)), however only those metabolites that retain the essential ring structures of the ergot alkaloids (the ergoline ring and the peptide side chain) are pharmacologically active. In this regard the major metabolite appears to be the 8′-OH DHE metabolite (Chen et al. J., Chromatography 768:267-275 (2002)) which is an active metabolite having pharmacologic effects that are qualitatively similar to that of the parent DHE compound (Moller-Schweinitzer E., Eur J Clin Pharmacol 26:699-705 (1984) and Hanoun et al., Br J Pharmacol 139:424-434 (2003)).